It has long been held that self-renewing tissues such as bone marrow are maintained by slowly cycling (largely quiescent) stem cells, which upon activation give rise to rapidly cycling progenitor cells. Recently, it has been established that a subpopulation of dormant stem cells (that rarely cycle) are also present, which seem to function primarily as potent stem cells following tissue injury. Under normal conditions, by comparison, dormant stem cells are thought to contribute only minimally to tissue homeostasis. The continuously self-renewing intestinal epithelium, in contrast, appears to be maintained by at least two separate stem cell populations under basal conditions, which are either rapidly cycling or slowly cycling. Using two strains of reporter mice, we now show that telomerase-expressing cells represent a rare population of dormant stem cells that are highly resistant to intestinal injury. As such, telomerase does not represent a universal marker for ISCs but rather marks a subpopulation of ISCs with potent regenerative capacity. Intriguingly, our preliminary data indicate that telomerase-expressing ISCs give rise to rapidly cycling Lgr5+ cells suggesting a lineage hierarchy within the intestinal crypt as well as a potential mechanism by which stem cells may be replaced following injury. This proposal seeks to further define the role of mTert-expressing cell in intestinal homeostasis and in response to injury as well as to examine the molecular basis for quiescence and self-renewal. The successful completion of these goals will provide an in depth understanding of the key regulatory pathways utilized by ISCs and potentially lead to novel therapeutic strategies for patients with gastrointestinal conditions such as inflammatory bowel disease, short bowel syndrome and intestinal cancer. PUBLIC HEALTH RELEVANCE: Slowly cycling tissue stem cells hold great promise for regenerative medicine and tissue repair, though have remained elusive in many tissues including intestine due to a lack of definitive biomarkers. We have employed an innovative strategy using transgenic mice that allows for the identification, isolate and genetic manipulate of intestinal stem cells. This work may give rise to novel therapeutic treatment strategies for intestinal diseases such as small bowel syndrome, inflammatory bowel disease and intestinal cancers.